A major problem in cancer chemotherapy is the emergence of drug- resistant cells. Chemotherapy-resistance is probably due to multiple mechanisms including altered uptake/excretion of drug, increased inactivation of drug, and altered host response such as increased DNA repair. We have initiated studies with a variety of human tumor cell lines which have been selected for resistance to cis-Pt diamminedichloride (DDP), nitrogen mustard (HN2), or other alkylating agents. Our initial studies have involved determining the level of different stress-induced transcripts in these chemoresistant tumor cell lines compared to their parent cell lines with normal sensitivity. Several examples of over-expression of certain of our DDI transcripts in DDP and alkylating agent resistant cells have been found. For example, in the case of gadd153 RNA, this transcript was constitutively elevated in HN2-resistant derivatives of a human tumor cell line, Raji/HN2. These studies raise the important possibility that over-expression of certain DNA-damage-inducible genes may play a role in chemotherapy resistance.